The patterns of response of individual cells to carcinogens may be a factor that influences the shape of the dose-response curve for cancer in human populations; thus the existence of a threshold for cellular response may imply a threshold for cancer induction. The patterns of response of cultured mammalian cells to carcinogen treatment is described for four cellular endpoints: cytotoxidty, mutation, sister chromatid exchange, and in vitro transformation. These data, taken in toto, indicate that for some carcinogens a threshold exists for the induction of cellular effects, but for some carcinogens thresholds probably do not exist. Cancer-prone human beings may contain cell populations without thresholds, making them especially sensitive to low doses of environmental carcinogens.
References
1.
1. Latt, S.A., Allen, J., Bloom, S.E., Carrano, A., Falke, E., Kram, D., Schneider, E., Schreck, R., Tice, R., Whitfield, B., and Wolff, S.Sister Chromatid Exchanges: A Report of the Cene-Tox Program. Mutat Res., 87: 17–62 (1981).
2.
2. Bradley, M.O., Bhuyan, B., Francis, M.C., Langenbach, R., Peterson, A.and Huberman, E. Mutagenesis by chemical agents in V79 Chinese hamster cells: A review and analysis of the literature. Mutat. Res., 87: 81–142 (1981).
3.
3. Report of the Cene-Tox Program. In Press Mutat Res.
4.
4. Thacker, J. and Cox, R.Mutation induction and inactivation in mammalian cells exposed to ionizing radiation. Nature, 258: 429–431 (1975).
5.
5. Carrano, A.V., Thompson, L.H., Lindl, Pa and Minkler, J.L.Sister chromatid exchange as an indicator of mutagenesis. Nature, 271: 551–3 (1978).
6.
6. Popescu, N.C., Amsbaugh, C.J., and DiPaolo, J.A.Relationship of carcinogen-induced sister chromatid exchange and neoplastic cell transformation. Int J. Cancer, 28: 71–7 (1981).
7.
7. Puck, T.T. and Marcus, P.I.Action of x-rays on mammalian cells. J. Expt Med., 703: 653–66 (1956).
8.
8. Williams, J.R. Survival of Human Cells Irradiated with Ultra Violet Light, Thesis, Harvard University, 1972.
9.
9. Maher, V.M., Ouellette, L.M., Curren, R.D. and McCormick, J.J.Frequency of ultraviolet light-induced mutations is higher in Xeroderma pigmentosum variant cells than in normal human cells. Nature, 261: 593–5 (1976).
10.
10. Robbins, J.H., Kraemer, K.H., Lutzner, M.A., Festoff, B.W. and Coon, H.C., Xeroderma pigmentosum, an inherited disease with sun sensitivity, multiple cutaneous neoplasms and abnormal Dna repair, Ann. Intern. Med., 80: 221–48 (1974).
11.
11. Williams, J.R. and D'Arpa, P.Epigenetic and genetic factors in the cellular response to radiations and DNA-damaging chemicals. J. Invest Derm.77: 125–32 (1981).
12.
12. Kleijer, W.J., Lohman, P.H.M., Mulder, M.P., Bootsma, D.Repair of x-ray damage in DNA of cultivated cells from patients having Xeroderma pigmentosum. Mutat Res.9: 517–23 (1970).
13.
13. Myhr, B.C., Turnbull, D. and DiPaolo, J.A.Ultraviolet mutagenesis of normal and Xeroderma pigmentosum variant human fibroblasts. Mutat Res.62: 341–53 (1979).
14.
14. Frank, J.P. and Williams, J.R.X-ray induction of a persistent hypersensitivity to mutation. Science, 216: 307–8 (1982).
15.
15. Van Zeeland, A.A. and Simons, J.W.I.M.Linear dose-response relationships after prolonged expression times in V79 Chinese hamster cells. Mutat Res.35: 129–38 (1976).
16.
16. Arlett, C.F., Turnbull, D., Harcourt, S.A., Lehmann, A.R. and Colella, C.M.A comparison of the 8-azaguanine and ouabain-resistance systems for the selection of induced mutant Chinese hamster cells. Mutat. Res.33: 261–78 (1975).
17.
17. Miller, J.A. and Miller, A.C.Ultimate chemical carcinogens as reactive mutagenic electrophiles IN: Origins of Human Cancer (Hiatt, H.H., Watson, J.D. and Winsten, J.A, Eds.) Cold Spring Harbor Laboratory (1977) pp 605–28.
18.
18. Cairns, J.The origin of human cancers. Nature, 289: 353–7 (1981).
19.
19. Reznikoff, C.A., Brankow, D.W., and Heidelberger, C.Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to post-confluence inhibition of cell division. Cancer Res.33: 3239–49 (1973).
20.
20. Barret, J.C., Bias, N.E. and Ts'o, P.O.P.A mammalian cellular system for the concomitant study of neo-plastic transformation and somatic mutation. Mutat Res.50: 121–36 (1978).
21.
21. Terzaghi, M. and Little, J.B.Repair of potentially lethal radiation damage in mammalian cells is associated with enhancement of malignant transformation. Nature, 253: 548–9 (1975).
22.
22. Chan, C.L. and Little, J.B.Induction of onocogenic transformation in vitro by ultraviolet lightNature, 264:442–4 (1976).
23.
23. Littlefield, Na, Farmer, J.H., Galflor, D.W. and Sheldon, C.W.Effects of dose and time in a long-term, low-dose carcinogenic study. In: Innovations in Cancer Risk Assessment (ED-01 Study) (Staffa, J.A. and Mehlman, M.A, Eds.) Pathotox Publishers, Inc., Illinois (1979). 19.
